Sphingosine 1-phosphate (S1P) is a lysophospholipid mediator that evokes a variety of cellular responses by stimulation of five members of the endothelial cell differentiation gene (EDG) receptor family. The EDG receptors are G-protein coupled receptors (GPCRs) and on stimulation propagate second messenger signals via activation of heterotrimeric G-protein alpha (Gα) subunits and beta-gamma (Gβγ) dimers. Ultimately, this S1P-driven signaling results in cell survival, increased cell migration and, often, mitogenesis. The recent development of agonists targeting S1P receptors has provided insight regarding the role of this signaling system in physiologic homeostasis. For example, the immuno-modulator, FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]propane 1,3-diol), that following phosphorylation, is an agonist at 4 of 5 S1P receptors, revealed that enhancing S1P tone influences lymphocyte trafficking. Further, S1P type 1 receptor (S1P1) antagonists cause leakage of the lung capillary endothelium, which suggests that S1P may be involved in maintaining the integrity of the endothelial barrier in some tissue beds. S1P is synthesized by the action of two enzymes, sphingosine kinase types 1 and 2 (SphK1, SphK2), in transferring a phosphate residue from ATP to sphingosine (the enzymes also catalyze the phosphorylation of sphinganine to yield sphinganine 1-phosphate (dihydroS1P)).
Sphingosine 1-phosphate (S1P) has been demonstrated to induce many cellular processes, including those that result in platelet aggregation, cell proliferation, cell morphology, tumor-cell invasion, endothelial cell chemotaxis and angiogenesis. For these reasons, sphingosine kinases are good targets for therapeutic applications such as wound healing and tumor growth inhibition.
The importance of sphingosine kinase 1 and 2 (SphK1 & SphK2) in survival and proliferation has also been recognized. SphK1 & SphK2 catalyze the phosphorylation of the endogenous lipid D-erythro sphingosine to sphingosine 1-phosphate (S1P). SphK1 & SphK2 are also responsible for the equilibrium between the anti-apoptotic S1P and its pro-apoptotic metabolic precursor sphingosine and its precursor, ceramide. Thus, SphK1 & SphK2 have been proposed to be important drug targets. However, only a small number of compounds have been shown to inhibit the sphingosine kinases, including DL-threo-dihydrosphingosine, N,N-dimethylsphingosine and short-chain DL-erythro-sphingosine analogues. However, these compounds are not suitable as in vivo inhibitors and cannot address questions concerning SphK mediated disease states.
Traditional methods of inhibiting sphingosine kinases have centered on targeting the ATP binding site of the kinase, a strategy that has enjoyed moderate success. However, such methods suffer from limited of selectivity across a wide array of kinases. Additionally, the sequence of the ATP binding domain of SphK1 & SphK2 is conserved across a number of diacylglycerol (DAG) kinase family members, rendering the traditional strategy problematic.
Currently, there is a need for novel, potent, and selective agents that inhibit the substrate-binding domain of the sphingosine kinases (e.g., human SphK1 and SphK2) that have enhanced potency, selectivity, and oral bioavailability. In addition, there is a need in the art for identification of, as well as the synthesis and use of such compounds. The present invention satisfies these needs.